Non-motor aspects of Parkinson's disease (PD) such as deficient sensation, perception, and cognition are a source of a significant decline in everyday function and quality of life. Among the most important of daily functions that is affected in PD is visuospatial ability, which enables the perceptual and cognitive comprehension and navigation of the visual environment. Deficits in this domain arise from pathological changes in high-order association areas of the brain as well as from defective input from more basic visual processing areas, reflecting dysfunction of specific aspects of corticostriatal loops. Of potential importance to understanding the visuospatial sequelae of PD is consideration of the side of initial motor impairment, as PD nearly always has unilateral onset of neurodegeneration, and the right hemisphere is especially engaged in many aspects of visuospatial processing. We aim to define the relation between basic vision and visuospatial problems in PD and to examine underlying neural changes. In particular, we aim to elucidate the causal role of specific corticostriatal structures in visuospatial cognition and to define functional connectivity between specific cortical areas and striatal regions. We hypothesize, first, that cognitive impairments in PD reflect dysfunction in corticostriatal loops involving the rostrodorsal caudate. Second, we hypothesize that side of motor symptom onset as well as hemifield presentation of visual stimuli predict the hemispheric laterality of hypoactivation in corticostriatal loops, with stronger effects for patients with onset on the left body side (LPD) (right basal ganglia) and for left visual hemifield presentation. Our third focus is on the relation of visual and visuospatial impairments to daily function, including gait, motoric freezing, subjective quality of life, hallucinations, mood and other patient-centered features of PD. To accomplish our goals, we will marshal the expertise of scientists from complementary disciplines, including neuropsychology, visual psychophysics, cognitive neuroscience and neuroimaging, and clinical movement science. Our proposed fMRI studies provide a direct test of the hypothesis that dysfunction in specific components of corticostriatal loops, especially frontostriatal and parietostriatal loops, underlie problems on specific visuospatial and visuocognitive tasks in PD. As most cortical regions are connected with the striatum, the studies will fill a significant gap in understanding the likely ubiquitous role of corticostriatal circuits in cognition. The application of psychophysical, cognitive and imaging techniques that could predict the integrity of higher-level cognitive and daily functions in PD will be useful clinically, enabling the identification of potential spatial problems for the patient at diagnosis. Our tests target visual, visuospatial, and functional symptoms reported by the patients themselves, ensuring that the elucidation of mechanisms will have clinical relevance. PUBLIC HEALTH RELEVANCE: A principal goal of the proposed project is to relate the neuroimaging, cognitive, and psychometric findings with patient-centered features of PD, including gait abnormalities and motor freezing, subjective quality of life, visual complaints, hallucinations, mood, and self-reported sleep quality. We plan to bridge the psychometric, cognitive and imaging findings to the functional measures, which we expect will lead to translations to diagnostic and management strategies. If visuospatial differences between PD subgroups (such as left and right symptom onset) distinguish their performance on functional measures, then we should target the more affected subgroup with information on what to expect and how best to manage the symptoms that are part of that subgroup's profile.